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Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate 214. Patients with aRCC (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC. • We report the longest follow-up (8 years) for a phase III first-line checkpoint inhibitor-based aRCC combination therapy. • Long-term OS remained superior with NIVO+IPI versus SUN in ITT patients (HR 0.72) and in patients with I/P risk (HR 0.69). • ORR benefits were maintained with NIVO+IPI versus SUN in ITT patients (39% and 33%) and I/P risk patients (42% and 27%). • In FAV-risk patients, the OS HR improved over 8 years (0.82) with NIVO+IPI versus SUN, with twice the complete response rate. • Fewer grade 3-4 treatment-related adverse events occurred in patients treated with NIVO+IPI versus SUN (48.4% versus 64.1%). [ABSTRACT FROM AUTHOR]

The current analysis aimed to evaluate the economic benefit of toripalimab plus axitinib for previously untreated RCC patients from the Chinese healthcare system perspective. The partitioned survival model was developed to simulate 3-week patients' transition in 20-year time horizon to evaluate the cost-effectiveness of toripalimab plus axitinib compared with sunitinib for advanced RCC. Survival data were gathered from the RENOTORCH trial, and cost and utility inputs were obtained from the database and published literature. Total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were the model outputs. Subgroup analyses and sensitivity analyses were conducted to increase the comprehensiveness and estimate the robustness of the model results. In the base-case analysis, compared with sunitinib, toripalimab plus axitinib could bring additional 1.19 LYs and 0.65 QALYs, with the marginal cost of $41,499.23, resulting in the ICER of $64,337.49/QALY, which is higher than the WTP threshold. And ICERs were always beyond the WTP threshold of all subgroups. Sensitivity analyses demonstrated the model results were robust. Toripalimab plus axitinib was unlikely to be the cost-effective first-line therapy for patients with previously untreated advanced RCC compared with sunitinib from the Chinese healthcare system perspective. [ABSTRACT FROM AUTHOR]

This real-world study of patients with renal cell carcinoma (RCC) compared clinical outcomes for patients treated with tyrosine kinase inhibitors (TKI), or an immunotherapy combination (IO + TKI or IO + IO). Medical record data was collected retrospectively for 498 patients across North America, Europe, and the UK. Immunotherapy (IO) combination was associated with longer progression-free survival (PFS) and time to next treatment (TTNT) than tyrosine kinase inhibitor (TKI) monotherapy. Among IO combinations, IO + TKI was associated with significantly improved progression-free survival (PFS) and TTNT compared to IO + IO. Background: Nearly 30% of new renal cell carcinoma (RCC) cases are diagnosed at an advanced or metastatic stage. Recent approvals of immunotherapies (IO) have significantly impacted patient care, but real-world outcomes of these treatments have not been widely evaluated. Methods: Eligible physicians abstracted demographic and clinical data from patient medical records for patients with advanced clear and non-clear cell RCC (aRCC) who initiated treatment between January 1, 2018, and December 31, 2020. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. A multivariate Cox regression model was developed to assess the impact of treatment category on clinical outcomes while controlling for International Metastatic RCC Database Consortium (IMDC) risk category, histology, and other patient characteristics. Results: A total of 498 patients were included (201 from US, 62 from Canada, 58 from UK, 59 from France, 58 from Germany, 60 from Spain). Of these, 250 received tyrosine kinase inhibitor (TKI) monotherapy, 197 received immunotherapy (IO) combination (119 IO + TKI, 78 IO + IO), and 32 received IO monotherapy as first-line treatment for aRCC; 19 patients received various other regimens. 16% of patients had a favorable IMDC risk score. Based on results of multivariable Cox regression, PFS (hazard ratio [HR] [95% confidence interval (CI)]: 0.50 [0.36-0.72]) (P < .001) and time to next treatment (TTNT) were significantly longer (HR [95% CI]: 0.54 [0.39-0.73]) (P < .001) for patients treated with IO combination versus TKI monotherapy. IO combination had a numerically reduced, but statistically insignificant, risk of death versus TKI monotherapy (HR: 0.66; P = .114). IO + TKI combination was associated with significantly longer PFS and reduced risk of progression (HR: 0.52; P = .04) versus IO + IO combination; similar results were observed for TTNT (HR: 0.57; P = .03). Conclusion: Our evaluation of realworld treatment outcomes in aRCC revealed that IO + TKI combination is associated with improved PFS and prolonged TTNT compared with TKI monotherapy and IO + IO combination. [ABSTRACT FROM AUTHOR]

The purpose of this study is to examine the cost-effectiveness of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy (NIVO + IPI) compared with the sunitinib (SUN) therapy for Japanese patients with advanced renal cell carcinoma from the perspective of a Japanese health insurance payer. A lifetime horizon was applied, and 2% per annum was set as the discount rate. The threshold was set as $ 75 000 per quality-adjusted life-year (QALY) gained. For the analytical method, we used a partitioned survival analysis model to estimate the incremental cost-effectiveness ratio (ICER), which is calculated by dividing incremental costs by incremental QALYs. Progression-free survival, progressive disease, and death were set as health states. Additionally, cost parameters and utility weights were set as key parameters. We set the intermediate/poor-risk population as the base case. Scenario analysis was conducted for the intention-to-treat population and the favorable risk population. Furthermore, one-way sensitivity analysis and probabilistic sensitivity analysis were conducted for each population. In the base-case analysis, the QALYs of NIVO + IPI and SUN were 4.32 and 2.99, respectively. NIVO + IPI conferred 1.34 additional QALYs. Meanwhile, the total costs in the NIVO + IPI and SUN were $692 288 and $475 481, respectively. As a result, the ICER of NIVO + IPI compared with SUN was estimated to be $162 243 per QALY gained. The parameter that greatly affected the ICER was the utility weight of progression-free survival in NIVO + IPI. NIVO + IPI for advanced renal cell carcinoma seems to be not cost-effective compared with the SUN in the Japanese healthcare system. • According to previous research, nivolumab plus ipilimumab (NIVO + IPI) for advanced renal cell carcinoma (aRCC) is cost-effective compared with sunitinib (SUN) in the United States and China but not in the United Kingdom. • Adding to the existing knowledge, we conducted a cost-effective analysis of NIVO + IPI compared with SUN for aRCC from the perspective of a "Japanese health insurance payer." • In Japanese patients with aRCC, NIVO + IPI might not be cost-effective compared with SUN under the Japanese insurance system. [ABSTRACT FROM AUTHOR]

Background: Although immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response to these agents remains poor. Some studies have shown that combination therapy including an ICI appears to be the best treatment; however, the overall benefit in terms of efficacy and toxicity still needs to be assessed. Thus, we performed a network meta-analysis to evaluate the differences in the efficacy of several combinations that include an ICI to provide a basis for clinical treatment selection. Methods: We conducted a thorough search of PubMed, EMBASE, and the Cochrane Library for articles from January 2010 to June 2023. R 4.4.2 and STATA 16.0 were used to analyze data; hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to assess the results. Results: An indirect comparison showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were the most effective treatments for progression-free survival (PFS), with no significant differences between the two interventions (HR, 1.31; 95% CI, 0.96-1.78; P=0.08); rank probability showed that pembrolizumab plus lenvatinib had a 57.1% chance of being the preferred treatment. In the absence of indirect comparisons between pembrolizumab plus axitinib, nivolumab plus ipilimumab, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, pembrolizumab plus axitinib (40.2%) was the best treatment option for overall survival (OS). Compared to pembrolizumab plus lenvatinib, nivolumab plus ipilimumab (OR, 0.07; 95% CI, 0.01-0.65; P=0.02) and pembrolizumab plus axitinib (OR, 0.05; 95% CI, 0.00-0.78; P<0.001) had a lower incidence of overall adverse events (AEs). Conclusion: Pembrolizumab plus lenvatinib and pembrolizumab plus axitinib resulted in the highest PFS and OS rates, respectively. Pembrolizumab plus axitinib may be the best option when AEs are a concern. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab–axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab–axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab–axitinib group and 58.6% of patients in the sunitinib group. In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile ClinicalTrials.gov NCT04394975 • Toripalimab plus axitinib provided significantly better PFS than sunitinib as a first-line treatment for advanced RCC. • A significantly higher ORR was found in patients who received toripalimab plus axitinib than those who received sunitinib. • The combination of toripalimab plus axitinib was generally well tolerated. • No new safety signals were identified in the combination outside the known safety profile of toripalimab or axitinib. [ABSTRACT FROM AUTHOR]

The need for biomarker in treatment of advanced RCC remains critical. We investigated the impact of duration exposure to antiangiogenic on clinical outcomes in 354 metastatic ccRCC treated with nivolumab in the NIVOREN-GETUG-AFU26 trial. Nivolumab activity in second line is independent from first-line duration of VEGFR TKI. No difference has been observed in 8 circulating soluble factors measured. Background: In metastatic renal clear cell carcinoma (ccRCC), vascular endothelial growth factor receptor (VEGFR) and immune checkpoint are 2 main therapeutic targets. We investigated the impact of duration exposure to antiangiogenic on immunotherapy clinical outcomes in metastatic ccRCC. Methods: Patients from NIVOREN trial who received nivolumab after only 1 prior antiangiogenic therapy were included. Response rate, clinical benefit, progression free survival (PFS) and overall survival (OS) were prospectively analyzed depending on the duration of the first line (< 6 months, =6 months) and exploratory in patients with long first line exposure (=18 months). The circulating levels of 8 plasma proteins and cytokines at baseline were collected and compared according to first line antiangiogenic duration. Results: Among 354 patients, 127 (36%) and 227 (64%) patients had received first line antiangiogenic for < 6months and = 6months respectively. Respective duration of first line therapy was not associated with objective response to nivolumab (20.5% vs. 23.9%, P = .50), or PFS (HR 0.92; P = .421). Median OS was respectively 16.6 and 31.3 months in the < 6 and =6 months subgroups respectively. Adjusted on international metastatic renal cell carcinoma database consortium risk, age and metastatic site, OS was longer in patients with longer treatment duration in the first line setting (HR 0.73; P = .017). Duration of first line VEGFR TKI was independent from circulating levels of 8 proteins and cytokines at nivolumab baseline. Conclusion: Nivolumab activity in second line is independent from first-line duration of VEGFR TKI. However, first line VEGFR TKI duration = 6 months is associated with longer OS. [ABSTRACT FROM AUTHOR]

Purpose: The field of immunotherapy combinations for advanced renal cell carcinoma (aRCC) has been expanded in recent years. However, the treatment response varies widely among individual patients. It is still a challenge to predict oncological outcome in clinical practice. We assessed the impact of an activated immune system reflected by changes in C-reactive protein (CRP) levels and the early onset of treatment-related adverse events (TRAEs) on the treatment response. Methods: In this retrospective analysis of 57 aRCC patients, CRP kinetics based on previous descriptions of CRP flare-response, CRP response or CRP non-response, and the TRAEs, which occurred within a month after therapy initiation, were obtained for this study. According to logistic regression analysis of both factors, we stratified the patients into risk groups: the presence of CRP flare-response/response and early onset of TRAE (low-risk group); the presence of a single factor (intermediate-risk group); and without both factors (high-risk group). Results: Ten patients (17%) experienced primary disease progression. No progressive disease was observed in the low-risk group, while 60% (n = 6/10) of the high-risk group showed a primary disease progression. Significantly, an increased risk of disease progression was observed by patients without CRP response and TRAEs (p < 0.001). Conclusion: The present analysis displays the predictive value of the on-treatment risk model based on CRP kinetics and the early onset of TRAEs, which can be easy to implement in clinical practice to optimize the treatment monitoring. [ABSTRACT FROM AUTHOR]

Background: In the treatment of advanced urothelial (aUC) and renal cell carcinoma (aRCC), biomarkers such as PD-1 and PD-L1 are not robust prognostic markers for immunotherapy (IO) response. Previously, a significant association between IO and a change in splenic volume (SV) was described for several tumour entities. To the best of our knowledge, this study presents the first correlation of SV to IO in aUC and aRCC. Methods: All patients with aUC (05/2017–10/2021) and aRCC (01/2012–05/2022) treated with IO at our academic centre were included. SV was measured at baseline, 3 and 9 months after initiation of IO using an in-house developed convolutional neural network-based spleen segmentation method. Uni- and multivariate Cox regression models for overall survival (OS) and progression-free survival (PFS) were used. Results: In total, 35 patients with aUC and 30 patients with aRCC were included in the analysis. Lower SV at the three-month follow-up was significantly associated with improved OS in the aRCC group. Conclusions: We describe a new, innovative artificial intelligence-based approach of a radiological surrogate marker for IO response in aUC and aRCC which presents a promising new predictive imaging marker. The data presented implicate improved OS with lower follow-up SV in patients with aRCC. [ABSTRACT FROM AUTHOR]

Lenvatinib plus pembrolizumab or everolimus have considerable clinical benefits. However, it is controversial whether the high-cost combination regimen will be approved by the guidelines and widely used in clinical practice. Based on current prices, lenvatinib plus pembrolizumab is a cost-effective treatment option. Our conclusions provide objective data reference for clinicians when making clinical decisions, individual treatment of patients, and reference for national health insurance decision-making. Introduction: The CLEAR trial indicated that survival benefits were generated with lenvatinib plus pembrolizumab (LP) or everolimus (LE) than with sunitinib for advanced renal cell carcinoma (aRCC). However, the high cost of immuno-target and dual-targeted treatment, we assessed the costeffectiveness of lenvatinib plus pembrolizumab or everolimus in the first-line setting for treatment of patients with aRCC from the United States (US) payers' perspective. Materials and Methods: A comprehensive Markov model was developed to evaluate the cost and effectiveness of LP or LE in first-line therapy for aRCC. We estimated life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). Utility values and direct costs related to the treatments were gathered from the published studies. Then, one-way and probabilistic sensitivity analyses were performed. Additional subgroup analyses were considered. Results: Treatment with LP and LE provided an additional 0.67 QALYs (0.62 LYs) and 0.66 QALYs (0.90 LYs) compared with sunitinib, resulting in ICER of $131,656 per QALY and 201,928 per QALY, respectively. The most influential factor in this model was the cost of pembrolizumab with LP. Probabilistic sensitivity analysis showed there was a 58.97% and 28.91% probability that LP and LE were cost-effective at WTP values of $150,000 per QALY in the US. Subgroup analyses demonstrated that LP was more cost-effective for patients from Western Europe and North America, intermediate risk of the International risk group of Metastatic Renal Cell Carcinoma Database Consortium (IMDC), favorable and intermediate risk group of Memorial Sloan Kettering Cancer Center (MSKCC) and PD-L1 combined positive score greater than or equal to 1%. Conclusion: From the perspective of the US payer, LP is a cost-effective option as first-line treatment for patients with aRCC at a WTP threshold of $150,000 per QALY, but LE is the opposite. [ABSTRACT FROM AUTHOR]

Background Despite 4 approved combination regimens in the first-line setting for advanced renal cell carcinoma (aRCC), adverse event (AE) costs data are lacking. Materials and Methods A descriptive analysis on 2 AE cost comparisons was conducted using patient-level data for the nivolumab-based therapies and published data for the pembrolizumab-based therapies. First, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib using data from the CheckMate 214 (median follow-up [mFU]: 13.1 months), CheckMate 9ER (mFU: 12.8 months), and KEYNOTE-426 (mFU: 12.8 months) trials, respectively. Second, grade 3/4 AE costs were compared between nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib using data from the CheckMate 214 (mFU: 26.7 months), CheckMate 9ER (mFU: 23.5 months), and KEYNOTE-581 (mFU: 26.6 months) trials, respectively. Per-patient costs for all-cause and treatment-related grade 3/4 AEs with corresponding any-grade AE rates ≥ 20% were calculated based on the Healthcare Cost and Utilization Project database and inflated to 2020 US dollars. Results Per-patient all-cause grade 3/4 AE costs for nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + axitinib were $2703 vs. $4508 vs. $5772, and treatment-related grade 3/4 AE costs were $741 vs. $2722 vs. $4440 over ~12.8 months of FU. For nivolumab + ipilimumab vs. nivolumab + cabozantinib vs. pembrolizumab + lenvatinib, per-patient all-cause grade 3/4 AE costs were $3120 vs. $5800 vs. $9285, while treatment-related grade 3/4 AE costs were $863 vs. $3162 vs. $5030 over ~26.6 months of FU. Conclusion Patients with aRCC treated with first-line nivolumab-based therapies had lower grade 3/4 all-cause and treatment-related AE costs than pembrolizumab-based therapies, suggesting a more favorable cost-benefit profile. [ABSTRACT FROM AUTHOR]

Nivolumab plus ipilimumab (NIVO + IPI) and pembrolizumab plus axitinib (PEM + AXI) have demonstrated significant clinical benefits as first-line (1 L) treatments for intermediate/poor-risk advanced renal cell carcinoma (aRCC) patients. This study aimed to assess the cost-effectiveness of NIVO + IPI versus PEM + AXI from a Brazilian private healthcare system perspective, utilizing a novel approach to estimate comparative efficacy between the treatments. A three-state partitioned survival model (progression-free, progressed, and death) was developed to estimate costs, life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-utility ratio (ICUR) over a 40-year time horizon. In the absence of head-to-head comparisons between NIVO + IPI and PEM + AXI, clinical data for NIVO + IPI was obtained from CheckMate 214 (NCT02231749) and for PEM + AXI from KEYNOTE-426 (NCT02853331). A matching-adjusted indirect comparison was conducted to account for the imbalance of treatment effect modifiers between the trials. Patient characteristics, resource use, health state utilities, and costs were based on Brazilian-specific sources. Costs and health outcomes were both discounted by 5% annually in line with Brazilian guidelines. The robustness of the results was evaluated through extensive sensitivity analysis and scenario analyses. When comparing the matched versus unmatched OS, PFS, and TTD curves there was no noteworthy difference. NIVO + IPI was associated with cost savings (R$ 350,232), higher LYs (5.54 vs. 4.61), and QALYs (4.74 vs. 3.76) versus PEM + AXI, resulting in NIVO + IPI dominating PEM + AXI. Key model drivers were the treatment duration for PEM, NIVO, and AXI. NIVO + IPI remained dominant in all scenario analyses, which indicated that model results were robust to alternative modelling inputs or assumptions. This analysis shows that NIVO + IPI is estimated to be a life-extending and potentially cost-saving 1 L treatment option when compared with PEM + AXI for intermediate/poor-risk a RCC patients in the Brazilian private healthcare system. Nivolumab plus ipilimumab (NIVO+IPI) and pembrolizumab plus axitinib (PEM+AXI) are currently the two most prescribed therapies in the Brazilian private healthcare market for the first-line (1L) treatment of intermediate/poor-risk advanced renal cell carcinoma (RCC) patients. Given that financial resources are limited, economic evaluations are needed to enable Brazilian payers to make informed decisions. In order to provide robust evidence on the relative costs and benefits of 1L RCC treatments in the Brazilian private healthcare system, the cost-effectiveness of NIVO+IPI versus PEM+AXI was evaluated using a three-state model. This model simulates the patient's journey, where a patient can remain free of disease progression, experience disease progression, or die. To reflect the Brazilian situation, patient characteristics, healthcare resource use and costs, and quality-of life data in the model were based on Brazilian sources. NIVO+IPI and PEM+AXI have not been compared "head-to-head" in a clinical trial, therefore treatment efficacy was estimated using a matching-adjusted indirect comparison, a method that uses patient-level data from one trial (Checkmate 214) to match summary patient characteristics from the comparator trial (KEYNOTE-426), thus enabling a robust comparison. Model results showed that NIVO+IPI was associated with cost savings (R$ 350,232), higher life-years (5.54 vs 4.61), and quality-adjusted life-years (4.74 vs 3.76) versus PEM+AXI, resulting in NIVO+IPI being less costly and providing more clinical benefits than PEM+AXI. By showing that NIVO+IPI is a life-extending and cost-saving 1L treatment option when compared with PEM+AXI for intermediate/poor-risk aRCC patients, this study can help Brazilian payers make value-based choices on their resource allocation. [ABSTRACT FROM AUTHOR]

Background: In the treatment of advanced urothelial (aUC) and renal cell carcinoma (aRCC), biomarkers such as PD-1 and PD-L1 are not robust prognostic markers for immunotherapy (IO) response. Previously, a significant association between IO and a change in splenic volume (SV) was described for several tumour entities. To the best of our knowledge, this study presents the first correlation of SV to IO in aUC and aRCC. Methods: All patients with aUC (05/2017–10/2021) and aRCC (01/2012–05/2022) treated with IO at our academic centre were included. SV was measured at baseline, 3 and 9 months after initiation of IO using an in-house developed convolutional neural network-based spleen segmentation method. Uni- and multivariate Cox regression models for overall survival (OS) and progression-free survival (PFS) were used. Results: In total, 35 patients with aUC and 30 patients with aRCC were included in the analysis. Lower SV at the three-month follow-up was significantly associated with improved OS in the aRCC group. Conclusions: We describe a new, innovative artificial intelligence-based approach of a radiological surrogate marker for IO response in aUC and aRCC which presents a promising new predictive imaging marker. The data presented implicate improved OS with lower follow-up SV in patients with aRCC.

First-line pembrolizumab + axitinib significantly improved overall survival, progression-free survival, and objective response rate over sunitinib, while health-related quality of life outcomes were not different between groups. In the phase 3 KEYNOTE-426 (NCT02853331) trial, pembrolizumab + axitinib demonstrated improvement in overall survival, progression-free survival, and objective response rate over sunitinib monotherapy for advanced renal cell carcinoma (RCC). To evaluate health-related quality of life (HRQoL) in KEYNOTE-426. A total of 861 patients were randomly assigned to receive pembrolizumab + axitinib (n = 432) or sunitinib (n = 429). HRQoL data were available for 429 patients treated with pembrolizumab + axitinib and 423 patients treated with sunitinib. HRQoL end points were measured using the European Organisation for the Research and Treatment of Cancer Core (EORTC) Quality of Life Questionnaire (QLQ-C30), EQ-5D visual analog rating scale (VAS), and Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index—Disease-Related Symptoms (FKSI-DRS) questionnaires. Better or not different overall improvement rates from baseline between pembrolizumab + axitinib and sunitinib were observed for the FKSI-DRS (–0.79% improvement vs sunitinib; 95% confidence interval [CI] –7.2 to 5.6), QLQ-C30 (7.5% improvement vs sunitinib; 95% CI 1.0–14), and EQ-5D VAS (9.9% improvement vs sunitinib; 95% CI 3.2–17). For time to confirmed deterioration (TTcD) and time to first deterioration (TTfD), no differences were observed between arms for the QLQ-C30 (TTcD hazard ratio [HR] 1.0; 95% CI 0.82–1.3; TTfD HR 0.82; 95% CI 0.69–0.97) and EQ-5D VAS (TTcD HR 1.1; 95% CI 0.87–1.3; TTfD HR 0.98; 95% CI 0.83–1.2). TTfD was not different between treatment arms (HR 1.1; 95% CI 0.95–1.3) for the FKSI-DRS, but TTcD favored sunitinib (HR 1.4; 95% CI 1.1–1.7). Patients were assessed during the off-treatment period for sunitinib, which may have underestimated the negative impact of sunitinib on HRQoL. Overall, patient-reported outcome scales showed that results between the pembrolizumab + axitinib and sunitinib arms were not different, with the exception of TTcD by the FKSI-DRS. Compared with sunitinib, pembrolizumab + axitinib delays disease progression and extends survival, while HRQoL outcomes were not different between groups. [ABSTRACT FROM AUTHOR]

Abstract Background Currently, immunotherapy is indicated for patients with metastatic RCC or unresectable RCC, but there is no indication for immunotherapy in the neoadjuvant setting. We report a case in which the combined use of nivolumab and ipilimumab and sequential TKI therapy enabled surgical treatment. Case presentation A 71-year-old female was diagnosed with a metastatic clear-cell renal cell carcinoma with a level IV tumor thrombus. She was started on nivolumab-ipilimumab therapy, and was switched to pazopanib monotherapy because the tumor thrombus progressed within the right atrium. The tumor shrank to resectable status with sequential therapy. She then underwent right nephrectomy and thrombectomy. Pathological analysis showed 10–20% residual tumor in the primary tumor, but no viable cells in tumor thrombus. She remains clinically disease-free 1 year after surgery. Conclusion This case suggests the utility of sequential immune-targeted therapy as neoadjuvant therapy in advanced renal cell carcinoma.

Abstract With the widespread use of PD‐1/PD‐L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD‐1/PD‐L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD‐L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD‐1/PD‐L1 mAb in the treatment of aRCC, and CTLA‐4 mAb has been shown to have a non‐redundant effect with PD‐1/PD‐L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD‐1/PD‐L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians’ select treatment options for patients with refractory kidney cancer.

The treatment regimen and prognosis of advanced renal cell carcinoma (RCC) have been changing rapidly in recent years with the advent of immune checkpoint inhibitors (ICIs) after the era of cytokine therapy and targeted therapy such as tyrosine kinase inhibitor (TKI). In the current situation where many effective drug therapies, especially TKIs, are available, it is important to carefully determine the timing and indications for nephrectomy for advanced RCC. On the other hand, data on the indications, timing, and safety of nephrectomy in the ICI era are still few and unclear. The number of cases in which nephrectomy is not appropriate or when to perform nephrectomy is expected to increase in the future. In this symposium, we mainly discussed the evolution of nephrectomy and then outlined the significance of nephrectomy in the era of ICI. [ABSTRACT FROM AUTHOR]

Over the last decade, there have been substantial progress in the field of systemic therapy for advanced renal cell carcinoma. Through the transition from treatment with cytokines to molecular‐targeted agents, and currently to immuno‐oncology drugs, the prognostic outcomes of patients with advanced renal cell carcinoma have been markedly improved. In particular, based on the promising outcomes of recently conducted pivotal randomized clinical trials, immuno‐oncology drug‐based combination therapy by either dual immune checkpoint inhibition or combined inhibition of an immune checkpoint and tyrosine kinase, is currently regarded as a standard of care for treatment‐naïve advanced renal cell carcinoma patients. However, insufficient data are available with respect to the selection of optimal systemic therapies for advanced renal cell carcinoma in the first‐line setting due to the lack of a head‐to‐head comparison between approved immuno‐oncology drug‐based combination therapies. In this review, therefore, we summarize interesting findings associated with first‐line combination therapies for advanced renal cell carcinoma obtained from both randomized clinical trials and real‐world clinical practices, in order to present useful guidance to help make treatment decisions for patients with treatment‐naïve advanced renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Background: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow‐up of 5 years. Methods: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6‐week cycles). Efficacy was assessed in intent‐to‐treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate‐risk/poor‐risk, and favorable‐risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. Results: The median follow‐up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression‐free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent‐to‐treat patients (N = 550 vs 546). Point estimates for 2‐year conditional overall survival beyond the 3‐year landmark were higher with NIVO+IPI versus SUN (intent‐to‐treat patients, 81% vs 72%; intermediate‐risk/poor‐risk patients, 79% vs 72%; favorable‐risk patients, 85% vs 72%). Conditional progression‐free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune‐mediated adverse event experience, body mass index, and age. Conclusions: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow‐up for a first‐line checkpoint inhibitor‐based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years. In the longest phase 3 follow‐up of a checkpoint inhibitor combination therapy in advanced renal cell carcinoma together with the first long‐term conditional survival analyses in the CheckMate 214 trial, nivolumab plus ipilimumab demonstrated durable survival and response benefits versus sunitinib at 5 years. These results establish a new benchmark for both the magnitude and durability of benefit possible with first‐line immunotherapy‐based regimens in this setting. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate the prognostic impact of trial-eligibility criteria on outcome in real-world metastatic renal cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors (TKIs). Patients and Methods: mRCC patients treated with TKIs as first-line systemic therapy were retrospectively evaluated. The patients were determined as trial-ineligible when they met at least 1 following trial-ineligible criteria; Karnofsky performance status score <70, hemoglobin <9.0 g/dL, creatinine >2.4 mg/dL (male) or >2.0 mg/dL (female), calcium >12.0 mg/dL, platelet <100,000 /μL, neutrophil <1,500 /μL, nonclear-cell histology, and brain metastasis. Results: Of 238 patients, 101 patients (42%) were determined as trial-ineligible. Progression-free survival (PFS) and overall survival (OS) after the TKI initiation were significantly shorter in the trial-ineligible patients than in the trial-eligible patients (median PFS: 5.53 vs. 15.8 months, p < 0.0001; OS: 13.8 vs. 43.4 months, p < 0.0001). Objective response rate was also significantly lower in the trial-ineligible patients (15% vs. 37%, p = 0.0003). Multivariate analysis further showed that the trial-eligibility was an independent factor for PFS (hazard ratio [HR]: 2.46, p < 0.0001) and OS (HR: 2.39, p < 0.0001). In addition, the number of trial-ineligible factors were negatively correlated with PFS and OS. Conclusions: In real-word, the substantial number of mRCC patients did not meet the trial-eligibility criteria, and their outcome was worse than that in the trial-eligible patients. Further studies focusing on the outcome in real-world trial-ineligible patients in the immune checkpoint inhibitor era are warranted. [ABSTRACT FROM AUTHOR]

In patients with advanced renal cell carcinoma without prior nephrectomy and with an evaluable primary tumor, combination immunotherapy with nivolumab plus ipilimumab offers a benefit in renal tumor reduction and survival over sunitinib. We present an exploratory post hoc analysis from the phase 3 CheckMate 214 trial of first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in a subgroup of 108 patients with advanced renal cell carcinoma (aRCC) without prior nephrectomy and with an evaluable primary tumor, a population under-represented in clinical trials. Patients with clear cell aRCC were randomized to NIVO+IPI every 3 wk for four doses followed by NIVO monotherapy, or sunitinib every day for 4 wk (6-wk cycle). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and primary tumor shrinkage were assessed. PFS and ORR were assessed per independent radiology review committee using RECIST version 1.1. With minimum study follow-up of 4 yr for intent-to-treat patients, OS favored NIVO+IPI (n = 53) over sunitinib (n = 55; hazard ratio 0.63, 95% confidence interval 0.40–1.0) among patients without prior nephrectomy. ORR was higher (34% vs 15%; p = 0.0041) and median duration of response was longer with NIVO+IPI versus sunitinib (20.5 vs 14.1 mo); the best overall response was partial response in either arm. A ≥30% reduction in the diameter of intact target renal tumors was achieved in 35% of patients with NIVO+IPI versus 20% with sunitinib. Safety was consistent with the global study population. In conclusion, in patients with aRCC without prior nephrectomy and with an evaluable primary tumor, NIVO+IPI showed survival benefits and renal tumor reduction versus sunitinib. This trial is registered at ClinicalTrials.gov as NCT02231749. In an exploratory analysis of a large global trial (CheckMate 214), we observed positive outcomes (both survival and tumor response to treatment) with nivolumab plus ipilimumab over sunitinib in a subgroup of patients with advanced kidney cancer who did not undergo removal of their primary kidney tumor. This subset of patients represents a population that has not been studied in clinical trials and for whom outcomes with new immunotherapy combination regimens are not yet known. We conclude that treatment with nivolumab plus ipilimumab offers these patients a survival benefit versus sunitinib, consistent with that observed in the overall study, as well as a notable kidney tumor reduction. [ABSTRACT FROM AUTHOR]

Immunotherapy has made great progress in the treatment of advanced renal cell carcinoma (RCC), since nivolumab was approved for the second-line therapy of advanced RCC. The efficacy of antiPD1 monotherapy was limited in the first-line setting, therefore the combination of immunotherapy and anti-angiogenesis targeted therapy is becoming the trend. As the release of several randomized phase Ⅲ clinical trials results, ipilimumab in combination with nivolumab is recommended for intermediate-/highrisk advanced RCC. Pembrolizumab plus axitinib or avelumab plus axitinib are proved to be more efficacious than traditional targeted therapy. How to select the appropriate population for immunotherapy depends on individual characteristics, disease risk, social economics and appropriate prognostic biomarkers.

Background: Nivolumab is the first immune checkpoint inhibitor approved in Europe for the treatment of advanced renal cell carcinoma (aRCC) in patients resistant to prior antiangiogenic therapy. WITNESS is an ongoing, prospective, observational study designed to evaluate the effectiveness and safety of nivolumab in patients with aRCC treated in real life (or routine practice) in France (ClinicalTrials.gov identifier: NCT03455452)., Patients and Methods: This study includes adult patients with a confirmed diagnosis of aRCC who have initiated nivolumab after 1-2 prior lines of antiangiogenic therapy. Endpoints include overall survival (OS), progression-free survival (PFS), duration of treatment (DOT), duration of response (DOR), overall response rate (ORR), subgroup analyses, and treatment-related adverse events (TRAEs). Results after a median follow-up of 12.3 months are presented here., Results: A total of 325 patients with aRCC were included, of whom 38.2% had a Karnofsky score <80, 77.8% received nivolumab as second-line therapy, and 69.5% had undergone a previous nephrectomy. In the overall population, median OS was 20.5 [95% confidence interval (CI) 17.6-25.0] months and median PFS was 5.2 (95% CI 4.5-5.9) months. ORR was 34.5%, median DOT was 3.8 months, and median DOR was 16.5 months. Nivolumab was effective in different subgroups including patients with bone or glandular metastases and those receiving baseline corticosteroids. Moreover, effectiveness was observed irrespective of prior nephrectomy and line of treatment. No new safety signals were identified; TRAEs of any grade were reported in 32.0% of patients, grade ≥3 and serious TRAEs in 11.1% each, and TRAEs leading to discontinuation in 8.9%., Conclusions: Preliminary results of the ongoing WITNESS study confirm the real-world effectiveness and safety of nivolumab monotherapy in previously treated patients with aRCC. Treatment benefits were similar to those observed in the pivotal phase III CheckMate 025 randomized clinical trial, despite a broader, real-life study population., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

With the widespread use of PD‐1/PD‐L1 monoclonal antibodies (mAbs) in the treatment of multiple malignant tumors, they were also gradually applied to advanced renal cell carcinoma (aRCC). Nowadays, multiple PD‐1/PD‐L1 mAbs, such as nivolumab, avelumab, and pembrolizumab, have achieved considerable efficacy in clinical trials. However, due to the primary, adaptive, and acquired resistance to these mAbs, the efficacy of this immunotherapy is not satisfactory. Theories also vary as to why the difference in efficacy occurs. The alterations of PD‐L1 expression and the interference of cellular immunity may affect the efficacy. These mechanisms demand to be revealed to achieve a sustained and complete objective response in patients with aRCC. Tyrosine kinase inhibitors have been proven to have synergistic mechanisms with PD‐1/PD‐L1 mAb in the treatment of aRCC, and CTLA‐4 mAb has been shown to have a non‐redundant effect with PD‐1/PD‐L1 mAb to enhance efficacy. Although combinations with targeted agents or other checkpoint mAbs have yielded enhanced clinical outcomes in multiple clinical trials nowadays, the potential of PD‐1/PD‐L1 mAbs still has a large development space. More potential mechanisms that affect the efficacy demand to be developed and transformed into the clinical treatment of aRCC to search for possible combination regimens. We elucidate these mechanisms in RCC and present existing combination therapies applied in clinical trials. This may help physicians' select treatment options for patients with refractory kidney cancer. [ABSTRACT FROM AUTHOR]

Background: Currently, immunotherapy is indicated for patients with metastatic RCC or unresectable RCC, but there is no indication for immunotherapy in the neoadjuvant setting. We report a case in which the combined use of nivolumab and ipilimumab and sequential TKI therapy enabled surgical treatment.Case Presentation: A 71-year-old female was diagnosed with a metastatic clear-cell renal cell carcinoma with a level IV tumor thrombus. She was started on nivolumab-ipilimumab therapy, and was switched to pazopanib monotherapy because the tumor thrombus progressed within the right atrium. The tumor shrank to resectable status with sequential therapy. She then underwent right nephrectomy and thrombectomy. Pathological analysis showed 10-20% residual tumor in the primary tumor, but no viable cells in tumor thrombus. She remains clinically disease-free 1 year after surgery.Conclusion: This case suggests the utility of sequential immune-targeted therapy as neoadjuvant therapy in advanced renal cell carcinoma. [ABSTRACT FROM AUTHOR]

In recent years, first-line therapies for metastatic renal cell carcinoma (mRCC) have shifted to a combination of immune checkpoint inhibitors or a combination of antiangiogenesis tyrosine kinase inhibitors (TKIs) and immunotherapy. This has led to a need to address standard-of-care treatment in the second-line setting. Our review presents an analysis of current and upcoming data to guide treatment decisions. After progression on nivolumab plus ipilimumab, current data favor monotherapy TKI with cabozantinib or axitinib. Current literature for second-line therapy given after combination TKI plus immunotherapy shows the strongest evidence for either single-agent cabozantinib or combination everolimus with lenvatinib. Investigations are ongoing for the role of TKIs with immunotherapy in the second-line setting. Novel agents, such as HIF2α inhibitors, are currently being studied as single agents and in combination with other treatment modalities in efforts to improve patient outcomes in mRCC. [ABSTRACT FROM AUTHOR]

Objective: To determine the safety and efficacy of cryoablation combined with sorafenib for the treatment of advanced renal cell carcinoma. Material and methods: We conducted an observational study in 156 patients with advanced renal cell carcinoma unsuitable for surgical treatment. Participants received cryoablation + sorafenib (n = 67) or sorafenib only (n = 89). Objective response rate (ORR), disease control rate (DCR), progression-free survival time (PFS), overall survival (OS), change in immune function after treatment, rate of adverse events, and quality of life were compared between the two groups. Results: In the cryoablation + sorafenib group, ORR and DCR were significantly higher and PFS and OS were significantly longer than in the sorafenib only group (both p .05). The incidence of targeted drug-related side effects was not significantly different between the groups (p > .05), and cryoablation did not increase the risk of side effects of targeted drugs. Conclusion: Cryoablation combined with sorafenib had superior clinical efficacy compared with sorafenib-only for the treatment of advanced renal cell carcinoma unsuitable for surgical treatment. Moreover, this combined therapy may enhance the body’s anti-tumor immunity and effectively prolong PFS and OS without compromising patient quality of life, thus representing a new treatment strategy for advanced renal cell carcinoma.

Objectives: Although axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab‐activated autologous dendritic cells–co‐cultured cytokine‐induced killer cells in patients with advanced RCC. Methods: All adult patients, including treatment‐naive or pretreated with VEGF‐targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab‐activated dendritic cells–co‐cultured cytokine‐induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter. Results: The 43 patients (22 untreated and 21 previously treated) showed a median progression‐free survival (mPFS) of 14.7 months (95% CI, 11.16–18.30). mPFS in treatment‐naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log‐rank P‐value = 0.07). Overall response rates were 25.6% (95% CI, 13.5–41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar‐plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long‐term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8+TIM3+ T cells and lower serum‐level immunostimulatory cytokine profile. Conclusions: The combination therapy was active and well tolerated for treatment of advanced RCC, either as first‐ or second‐line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers. [ABSTRACT FROM AUTHOR]

Abstract Objectives Although axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab‐activated autologous dendritic cells–co‐cultured cytokine‐induced killer cells in patients with advanced RCC. Methods All adult patients, including treatment‐naive or pretreated with VEGF‐targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab‐activated dendritic cells–co‐cultured cytokine‐induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter. Results The 43 patients (22 untreated and 21 previously treated) showed a median progression‐free survival (mPFS) of 14.7 months (95% CI, 11.16–18.30). mPFS in treatment‐naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log‐rank P‐value = 0.07). Overall response rates were 25.6% (95% CI, 13.5–41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar‐plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long‐term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8+TIM3+ T cells and lower serum‐level immunostimulatory cytokine profile. Conclusions The combination therapy was active and well tolerated for treatment of advanced RCC, either as first‐ or second‐line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers.

Aim: Assessing treatment patterns, outcomes and clinical characteristics in advanced renal cell carcinoma clinical practice. Materials & methods: A US cross-sectional physician survey conducted February-September 2019. Results: Surveyed physicians reported first-line treatment of 445 patients involving tyrosine kinase inhibitor monotherapy (51.0%), immuno-oncology (IO/IO combination) therapy (25.8%) or other regimens (23.1%). A total of 60.9% had physician-assessed IMDC risk. Of these 61.9, 50.9 and 27.6% of patients with favorable, intermediate and poor risk, respectively, received tyrosine kinase inhibitor monotherapy. A total of 16.7, 26.9 and 34.5% of patients with favorable, intermediate or poor risk received IO/IO combination therapy. Complete/partial responses (∼35% patients) remained comparable across first-line treatments. Conclusion: Guideline-recommended therapies are not widely prescribed. Many patients experienced poor clinical outcomes highlighting a need for more effective treatments. [ABSTRACT FROM AUTHOR]

Objective Anlotinib is an oral multi-target tyrosine kinase inhibitor (TKI) with dual effects of anti-proliferation and anti-angiogenesis. Phase Ⅰ clinical trials showed anlotinib was well tolerated and had therapeutic effects on a variety of tumors. The aim of this study is to explore the safety and efficacy of anlotinib in the treatment of metastatic renal cell carcinoma. Methods Between January 2014 and November 2015, a single-center data was obtained from a phase Ⅱ clinical study of anlotinib versus sunitinib on advanced renal cell carcinoma and a phase Ⅱ clinical study of anlotinib on advanced renal cell carcinoma which failed to respond to TKI treatment. Kaplan-Meier method was used for survival analysis, while Log-rank test was used to compare the survival rates. Results A total of 36 patients with advanced renal cell carcinoma were enrolled in this study, including 19 patients without any target drug treatment, 12 patients with sunitinib treatment and 5 patients with sorafenib treatment. The median number of treatment cycle was 16. Partial response (PR) was obtained in 11 patients (30.6%) and stable disease (SD) was obtained in 24 patients (66.7%). The disease control rate (DCR) was 97.2%. The median progression free survival (PFS) was 12.6 months, the 1-year survival rate was 80.6%, and the median survival time was 22.2 months. Up to the follow-up deadline, 3 patients still received treatment, the PFSs were 52.6 months, 65.0 months, and 66.7 months. The most common treatment-related adverse events of grade 3 or 4 included hypertension (19.4%), hand-foot skin reaction (11.1%), proteinuria (5.6%) and anemia (5.6%). Conclusions Anlotinib shows good anti-tumor activity and is generally well-tolerated in the treatment of advanced renal cell carcinoma. The adverse reactions of anlotinib are milder than sunitinib or pazopanib. [ABSTRACT FROM AUTHOR]

Introduction: The incidence of advanced renal cell carcinoma (RCC) is increasing. Over the last 10 years targeted therapies have led to improved efficacy outcomes for renal carcinoma, including longer survival. However, the majority of patients develop disease progression within a year of initiation of first-line therapy. Recently a number of new regimens have been investigated including the combination of immune checkpoint inhibitors with VEGF inhibitors.Areas covered: In this review, we assess the efficacy and safety of avelumab/axitinib in treatment-naïve patients with metastatic RCC and compare this combination to other current and emerging treatment regimens. In the Javelin 101 phase III registration trial, avelumab/axitinib demonstrated superior response rates and progression-free survival compared to sunitinib. However, after follow-up of 11.6 months, there was no significant difference in overall survival (OS). Avelumab/axitinib showed a tolerable safety profile. Adverse events were manageable and were in line with expected toxicities from the single agents.Expert Opinion: Avelumab/axitinib has shown impressive efficacy and a tolerable safety profile in metastatic RCC. The future role of this treatment combination in the rapidly evolving landscape of novel combinations in this disease will have to be defined. [ABSTRACT FROM AUTHOR]

Insights into the biology of advanced renal cell carcinoma (aRCC) and the development of agents targeting the vascular endothelial growth factor (VEGF) pathway have positively impacted the outcomes for patients with aRCC. With the recent approval of the dual immune checkpoint inhibitors (ICIs), nivolumab and ipilimumab, by the U.S. Food and Drug Administration (USFDA), and the European Medicines Agency (EMA), the era of VEGF monotherapy for untreated aRCC appears to be coming to an end for patients with access to the combination therapy. The frontline treatment options for renal cell carcinoma are evolving rapidly and will lead to the approval of other combination immunotherapies—especially those with VEGF inhibitors. Here we review the clinical data for dual immune checkpoint inhibition with nivolumab plus ipilimumab as well as the emerging data for ICI plus VEGF inhibitor combinations and discuss the challenges these will pose for the clinical practitioner.

Background: Although immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response to these agents remains poor. Some studies have shown that combination therapy including an ICI appears to be the best treatment; however, the overall benefit in terms of efficacy and toxicity still needs to be assessed. Thus, we performed a network meta-analysis to evaluate the differences in the efficacy of several combinations that include an ICI to provide a basis for clinical treatment selection., Methods: We conducted a thorough search of PubMed, EMBASE, and the Cochrane Library for articles from January 2010 to June 2023. R 4.4.2 and STATA 16.0 were used to analyze data; hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to assess the results., Results: An indirect comparison showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were the most effective treatments for progression-free survival (PFS), with no significant differences between the two interventions (HR, 1.31; 95% CI, 0.96-1.78; P=0.08); rank probability showed that pembrolizumab plus lenvatinib had a 57.1% chance of being the preferred treatment. In the absence of indirect comparisons between pembrolizumab plus axitinib, nivolumab plus ipilimumab, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, pembrolizumab plus axitinib (40.2%) was the best treatment option for overall survival (OS). Compared to pembrolizumab plus lenvatinib, nivolumab plus ipilimumab (OR, 0.07; 95% CI, 0.01-0.65; P=0.02) and pembrolizumab plus axitinib (OR, 0.05; 95% CI, 0.00-0.78; P<0.001) had a lower incidence of overall adverse events (AEs)., Conclusion: Pembrolizumab plus lenvatinib and pembrolizumab plus axitinib resulted in the highest PFS and OS rates, respectively. Pembrolizumab plus axitinib may be the best option when AEs are a concern., Systematic Review Registration: https://inplasy.com/, identifier INPLASY202410078., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Xu, Wu, Xie, Wang and Liu.)

Background: En bloc removal of the kidney with tumor thrombus excision in a multidisciplinary team remains the standard treatment for renal cell carcinoma (RCC) with tumor thrombus extension. In order to minimize the hemodynamic impact of the surgical blood loss, intraoperative cell salvage (IOCS) techniques can decrease the need for allogeneic blood and prevent blood transfusion related complications., Objective: In this article, we evaluated the safety of IOCS during radical nephrectomy with inferior vena cava thrombectomy under cardiopulmonary bypass with or without deep hypothermic circulatory arrest., Design and Method: In this retrospective comparative multicenter analysis, clinical characteristics of 27 consecutive patients who underwent surgery with or without IOCS between 2012 and 2022 in three referral care units were collected into a database. The need for an allogenic blood transfusion (ABT) was also recorded, defined as any transfusion that occurred either intraoperatively or during the hospital stay., Results: The need for ABT in the cell saver arm was significantly smaller due to the reinfusion of rescued blood ( p  < 0.015). In multivariate analysis, no cell saver usage was an independent predictor for complications ⩾3 Clavien 3a [odds ratio (OR) 18.71, 95% CI 1.056-331.703, p  = 0.046]. No usage of IOCS was an independent predictor for a lower risk of death (OR 0.277, 95% CI 0.062-0.825, p  = 0.024). During follow-up, patients who received salvaged blood did not experience an increased risk for developing local recurrence or distant metastases., Conclusion: Transfusion of autologous blood is safe and can be using during nephrectomy and thrombectomy for advanced RCC., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS). Patients and methods Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases. Results A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8–14.0) versus 5.3 months (95% CI 3.0–8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31–0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0–30.8) versus 9% (95% CI 3.7–17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6–not estimable) with cabozantinib and 21.2 months (95% CI 16.3–27.4) with sunitinib (HR 0.80 [95% CI 0.53–1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib. Conclusions In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk. Trial Registration Number NCT01835158 . [ABSTRACT FROM AUTHOR]